Background/Purpose: The activation of the complement system contributes essentially to its pathogenesis by autoantibody-antigen recognition directed against host cells in anti-neutrophil cytoplasmic antibody (ANCA)-associated renal vasculitis. The measurement of serum complement C3 with immunoassays is routinely used in clinical practice to determine and monitor complement activation. Importantly, C3 hypocomplementemia is only present in a minor subset of ANCA-associated renal vasculitis. These observations suggest that intrarenal synthesis of distinct complement components might contribute to kidney injury in renal vasculitis.

Methods: Intrarenal complement C3c localized to distinct vascular compartments (including small-sized arteries, capillaries, and venules) was evaluated in a total number of 43 kidney biopsies with ANCA-associated renal vasculitis. Publicly available transcriptome array datasets for C3 expression (encoded by C3) from Nephroseq (www.nephroseq.org, May 2022, University of Michigan, Ann Arbor, MI).

Results: Immunostaining confirmed presence of C3c deposits localized to either the glomerular tuft, interlobular arteries, peritubular capillaries, or venules in ANCA-associated renal vasculitis. Glomerular C3c deposits correlated positively with serum levels of complement C3c (p=0.011), further supporting intrarenal synthesis of complement C3. As compared to healthy controls, we observed a significant induction of C3mRNA transcripts in the tubulointerstitial (p< 0.0001) and glomerular compartments of renal vasculitis (p< 0.0001). Interestingly, intrarenal synthesis of C3 was significantly higher in renal vasculitis as compared to lupus nephritis for both compartments (p< 0.0001 and p< 0.001, respectively). Intrarenal C3 mRNA expression correlated with impaired kidney function in the tubulointerstitial and glomerular compartments of renal vasculitis. Gene set enrichment analysis linking intrarenal C3 synthesis to distinct inflammatory signaling pathways.

Conclusion: To our knowledge, this is the first report of a systematic analysis of intrarenal synthesis and vascular distribution of intrarenal complement C3 deposits in ANCA-associated renal vasculitis. This is especially relevant because clinical trials currently investigate inhibition of the complement system in ANCA-associated renal vasculitis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/intrarenal-synthesis-of-complement-c3-localized-to-distinct-vascular-compartments-in-anca-associated-renal-vasculitis/